Xie Baoping, Xin Liuyan, Liu Wen, Li An, Jin Qi, Xu Shuping, Hu Gonghua
Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Gannan Medical University), Ministry of Education, Jiangxi Provincial Key Laboratory of Tissue Engineering, Gannan Medical University, Jiangxi, 341000, PR China.
First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
Chem Biol Interact. 2025 Oct 22;420:111671. doi: 10.1016/j.cbi.2025.111671. Epub 2025 Jul 23.
Cerium chloride (CeCl), a prevalent by-product of rare earth mining, accumulates in the biota and environment of mining regions, including plants, animals, water resources, and air, posing potential health risks to local residents. Atherosclerosis (AS) is the pathological basis of cardiovascular disease. However, the relationship between subchronic CeCl exposure and AS progression, along with the underlying regulatory mechanisms by which CeCl modulates AS, remains unclear. In this study, we first demonstrated confirmed that CeCl significantly exacerbated AS plaque formation in ApoE mice fed with high-fat diet (HFD). Moreover, CeCl elevated serum levels of triglycerides (TG), cholesterol (CHO), and low-density lipoprotein (LDL). Further studies showed that CeCl significantly inhibited the expression of key regulators of ferroptosis, such as GPX4 and FTH1, as well as antioxidant enzyme glutathione peroxidase 4 (GPx4) and superoxide dismutase (SOD), and upregulated the levels of lipid peroxidation markers, including reactive oxygen species (ROS), malondialdehyde (MDA), and ferrous iron (Fe). Besides, CeCl significantly inhibited the expression of Nrf2, NQO1, and HO-1, and impeded Nrf2 nuclear translocation. Mechanistically, CeCl significantly promoted the formation of the Keap1/Nrf2 complex, leading to ubiquitin-mediated Nrf2 degradation. Pharmacological activation of Nrf2 by NK-252 significantly reduced CeCl-induced inhibition of GPX4 and FTH1 expression, and reversed its pro-atherosclerotic effects. Dual-luciferase reporter assays confirmed Nrf2 as a transcriptional regulator of GPX4. Taken together, our study demonstrates that CeCl exacerbates HFD-induced AS plaque formation and promotes ferroptosis in macrophages via the Keap1/Nrf2/GPX4 signaling pathway, providing new insights into strategies for preventing cardiovascular diseases with subchronic exposure to CeCl.
氯化铈（CeCl）是稀土开采中常见的副产物，会在矿区的生物群和环境中蓄积，包括植物、动物、水资源和空气，对当地居民构成潜在健康风险。动脉粥样硬化（AS）是心血管疾病的病理基础。然而，亚慢性CeCl暴露与AS进展之间的关系，以及CeCl调节AS的潜在调控机制仍不清楚。在本研究中，我们首先证实CeCl显著加剧了高脂饮食（HFD）喂养的ApoE小鼠的AS斑块形成。此外，CeCl升高了血清甘油三酯（TG）、胆固醇（CHO）和低密度脂蛋白（LDL）水平。进一步研究表明，CeCl显著抑制铁死亡关键调节因子如GPX4和FTH1的表达，以及抗氧化酶谷胱甘肽过氧化物酶4（GPx4）和超氧化物歧化酶（SOD），并上调脂质过氧化标志物的水平，包括活性氧（ROS）、丙二醛（MDA）和亚铁（Fe）。此外，CeCl显著抑制Nrf2、NQO1和HO-1的表达，并阻碍Nrf2核转位。机制上，CeCl显著促进Keap1/Nrf2复合物的形成，导致泛素介导的Nrf2降解。NK-252对Nrf2的药理激活显著降低了CeCl诱导的GPX4和FTH1表达抑制，并逆转了其促动脉粥样硬化作用。双荧光素酶报告基因检测证实Nrf2是GPX4的转录调节因子。综上所述，我们的研究表明CeCl通过Keap1/Nrf2/GPX4信号通路加剧HFD诱导的AS斑块形成并促进巨噬细胞铁死亡，为预防亚慢性CeCl暴露所致心血管疾病的策略提供了新见解。
